DESCRIPTION: (Applicant's Description)This research program (CA-19033), now in its twenty-fourth year, embodies ourlong-term commitment to the characterization and efficient, enantioselective synthesis of architecturally challenging anticancer agents. The principal goals for the 25-28 years are: (A) to complete and then refine the total synthesis of phorboxazole A (33) in order to prepare 1 gram of this rare natural product required for further biological evaluation; (B) to assign the relative and absolute stereochemisty of the marine macrolide zampanolide (37) via synthesis; (C) to develop a viable synthetic approach to apicularen A (38)a novel highly potent tumor cell-growth inhibitor; (D) to devise an efficient and highly convergent synthetic strategy for peloruside A (39), an architecturally complex marine macrolide, recently shown to exhibit potent cytotoxicity against murine leukemia. In conjunction with our interest in the synthesis of novel anticancer agents, we will also conduct a study of the remarkable olefin metathesis dimerization discovered during our cylindrocyclophane synthesis. Specifically, we will (E) carry out experiments designed to demonstrate the reversibility of the metathesis dimerization event; (F) conduct a computational study of the relative stability of the possible reaction products, thereby providing support for our mechanistic arguments; and (G) extend the concept of olefin cross-metathesis dimerization to other substrates. Finally, we will(H) develop an improved oxazole ring assembly discovered during our phorboxazole syntheticventure; application of this linchpin holds considerable promise for the construction of oxazole-containing natural products of biological interest. Beyond the specific synthetic objectives, a general, long-range aim of this program is the identification of the molecular architecture responsible for biological activity in these and related systems. Thus, as we develop an approach to each target structure, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships. The design of new and possibly more effective agents should then be feasible.